title: Microsomal epoxide hydrolase (EPHX1) polymorphisms are associated with aberrant promoter methylation of ERCC3 and hematotoxicity in benzene-exposed workers.
abstract: Benzene is an important industrial chemical and widespread environmental pollutant known to induce leukemia and other blood disorders. To be carcinogenic, benzene must be metabolized to produce toxic metabolites. To investigate whether single nucleotide polymorphisms (SNPs) in the metabolic enzyme genes are associated with benzene-induced alterations in DNA methylation and hematotoxicity, we genotyped four commonly studied SNPs in three metabolic enzymes genes CYP1A1, EPHX1 and NQO1; and analyzed promoter DNA methylation status in 11 genes which have been reported to be associated with benzene-induced hematotoxicity (BLM, CYP1A1, EPHX1, ERCC3, NQO1, NUDT1, p15, p16, RAD51, TP53 and WRAP53) in 77 benzene-exposed workers and 25 unexposed controls in China. ERCC3, a DNA repair gene, showed a small but statistically significant increase of promoter DNA methylation in the exposed group compared with the unexposed group (mean ± SD: 4.73 ± 3.46% vs. 3.63 ± 1.96%, P = 0.048). We also observed that an increased number of C allele for rs1051740 in EPHX1 was associated with decreased ERCC3 methylation levels in benzene-exposed workers (P(trend)  = 0.001), but not in unexposed controls (P(trend)  = 0.379). Interestingly, another EPHX1 SNP (rs2234922) was associated with lower white blood cell (WBC) counts (P(trend)  = 0.044) in benzene-exposed workers. These associations remained the same when ERCC3 promoter methylation and WBCs were dichotomized according to the 90th percentile (≥6%) of methylation levels in controls and a leucopenia cutoff (<4 × 10(9) /L), respectively. Our findings suggest that benzene exposure may be associated with hypermethylation in ERCC3, and that genetic variants in EPHX1 may play an important role in epigenetic changes and hematotoxicity among benzene-exposed workers.
authors.affiliation: Department of Occupational and Environmental Health Sciences, Peking University School of Public Health, Beijing, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Xing
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
authors.forename: Linyuan
authors.initials: L
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Zhengyong
authors.initials: Z
authors.lastname: Zou
authors.forename: Lifang
authors.initials: L
authors.lastname: Hou
authors.forename: Qian-Fei
authors.initials: QF
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Xinbiao
authors.initials: X
authors.lastname: Guo
mesh_terms: D001554:Benzene / Q000633:toxicity*; D002681:China; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004785:Environmental Pollutants / Q000633:toxicity*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006402:Hematologic Diseases / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D016273:Occupational Exposure; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; C072022:XPBC-ERCC-3 protein; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human; D004265:DNA Helicases; D001554:Benzene
keywords: ERCC3; genetic polymorphism; methylation; microsomal epoxide hydrolase; occupational exposure